Cyclopropyl benzyl ketone compounds of general formula (II) are important starting compounds of tetrahydro thienopyridine derivatives, which are used in the pharmaceutical therapy. One of the most important representatives of tetrahydro thienopyridine derivatives is compound of formula (I), namely 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-2-yl acetate, having the international non-proprietary name prasugrel, used for the prevention and treatment of thrombosis and thromboembolism.
The platelet inhibitor prasugrel, its derivatives, and the process for their preparation was described for the first time by Hungarian Patent No. 218 785 and Hungarian Patent No. 211 876. The object of the present invention relates to a process for the preparation of cyclopropyl benzyl ketone compounds of formula (II) in high purity, constituting a very important structural part of the above mentioned compounds. The process is very well-applicable on industrial scale.
In the preparation process of prasugrel, and the effective platelet inhibitor compounds having a similar chemical structure, the key intermediates are the ketone compounds of general formula (II), which can have different substituents on the aromatic ring. The most important representatives of these compounds are the halogen substituted derivatives, especially those substituted by chlorine or fluorine atoms. From the literature only a few preparation processes of these derivatives are known which are narrowly applicable on industrial scale.
According to the preparation process described in Hungarian Patent No. 218 785 and Hungarian Patent No. 211 876 cyclopropyl benzyl ketone compounds of formula (II) are prepared by the reaction of 2-fluorobenzyl magnesium bromide or 2-chlorobenzyl magnesium bromide and cyclopropanecarbonitrile. The reaction is carried out at the boiling point of diethyl ether, and the obtained complex is quenched with aqueous ammonium chloride, the product is extracted and purified by column chromatography. The yield of the process is 70% or 69%, respectively.
Hungarian Patent No. 211 876 also describes another process, wherein the compound of 2-fluorobenzyl magnesium halogenide is reacted, instead of cyclopropanecarbonitrile, with an acid chloride, for example cyclobutanecarbonyl chloride. The reaction is carried out at a very low temperature (−70° C.), and the pure product is obtained by extraction and purification by column chromatography. The yield of the process is very low, 39%.
In the above mentioned Grignard reactions for the preparation of compounds of formula (II) it is possible that the ester, nitrile or acid chloride reagents react with two equivalents of the Grignard reagent, instead of one. These reactions reduce the yield of the manufacturing process, and some by-products, containing a hydroxyl group, can be derived from the process.
In the preparation processes described in Hungarian Patents No. 218 785 and 211 876, the Grignard reagents are obtained from bromo derivatives. According to the present invention, in the preparation process of cyclopropyl benzyl ketone compounds of formula (II), the Grignard reagent is obtained from the more suitable and cheaper 2-fluorobenzyl chloride instead of 2-fluorobenzyl bromide. Among the halogen derivatives, the use of chloro derivatives is more economical, because they are cheaper and the applied amount is less, because they have a lower molecular weight than the bromo derivatives.
Preparation processes described in Hungarian Patent No. 211 876 are not suitable for the preparation of a drug on industrial scale, because the purification is carried out by column chromatography and this purification process is not suitable for the preparation of a large quantity of the final product. A large amount of reagents is needed for the purification therefore the process is more expensive and also very pollutive for the environment.
Another disadvantage of the reactions known from the literature is that the carboxylic acid derivatives, namely the acid chlorides and the anhydrides—see the description of Hungarian Patent No. 211 876—react with benzylmagnesium bromide at a very low temperature, at −70-−50° C. Therefore these processes—beyond the difficulties caused by the purification of column chromatography—are hardly applicable on an industrial scale and are energy-consuming and expensive reactions.
In U.S. Pat. No. 5,874,581 a process is described for the preparation of compound of formula (III), wherein two equivalents of 2-propyl magnesium chloride are reacted with 2-fluoroacetic acid in tetrahydrofuran, at the boiling point of the solvent. The obtained complex is reacted at a temperature of 5° C. with ethyl or methyl cyclopropanecarboxylate. The reaction mixture is stirred for three hours and hydrochloric acid is added, then the mixture is neutralized, extracted, evaporated, and finally the fractions are obtained in vacuo.
The disadvantage of the preparation process described in U.S. Pat. No. 5,874,581 is that very expensive starting materials and more than two equivalents of the Grignard reagent are used in the synthesis. The yield of the reaction is 56%, the purity of the final product is not mentioned.